Nociceptin analogs

ABSTRACT

The invention relates to benzothiadiazole compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein R 1 , R 2 , A, B, C, W, Z and n are defined as set forth in the specification. The compounds of the invention have affinity for the nociceptin receptor. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to modulation of the nociceptin receptor. Compounds of the present invention are especially useful for treating pain.

This application is a divisional of U.S. application Ser. No. 10/126,507filed Apr. 18, 2002 (U.S. Pat. No. 6,861,421), which claims priorityfrom U.S. Provisional Application Ser. Nos. 60/284,674 and 60/284,676,both filed Apr. 18, 2001, the disclosures of which are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

Chronic pain is a major contributor to disability and is the cause of anuntold amount of suffering. The successful treatment of severe andchronic pain is a primary goal of the physician with opioid analgesicsbeing preferred drugs.

Until recently, there was evidence of three major classes of opioidreceptors in the central nervous system (CNS), with each class havingsubtype receptors. These receptor classes were designated as μ, δ and κ.As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

Recent experimentation has led to the identification of a cDNA encodingan opioid receptor-like (ORL1) receptor with a high degree of homologyto the known receptor classes. This newly discovered receptor wasclassified as an opioid receptor based only on structural grounds, asthe receptor did not exhibit pharmacological homology. It was initiallydemonstrated that non-selective ligands having a high affinity for μ, δand κ receptors had low affinity for the ORL1. This characteristic,along with the fact that an endogenous ligand had not yet beendiscovered, led to the term “orphan receptor”.

Subsequent research led to the isolation and structure of the endogenousligand of the ORL1 receptor. This ligand is a seventeen amino acidpeptide structurally similar to members of the opioid peptide family.

The discovery of the ORL1 receptor presents an opportunity in drugdiscovery for novel compounds which can be administered for painmanagement or other syndromes modulated by this receptor.

All documents cited herein, including the foregoing, are incorporated byreference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of certain embodiments of the presentinvention to provide new compounds which exhibit affinity for the ORL1receptor.

It is an object of certain embodiments of the present invention toprovide new compounds which exhibit affinity for the ORL1 receptor andone or more of the μ, δ or κ receptors.

It is an object of certain embodiments of the present invention toprovide new compounds for treating a patient suffering from chronic oracute pain by administering a compound having affinity for the ORL1receptor.

It is an object of certain embodiments of the present invention toprovide new compounds which have agonist activity at the μ, δ and κreceptors which is greater than compounds currently available e.g.morphine.

It is an object of certain embodiments of the present invention toprovide methods of treating chronic and acute pain by administeringcompounds which have agonist activity at the μ, δ and κ receptors whichis greater than compounds currently available.

It is an object of certain embodiments of the present invention toprovide methods of treating chronic and acute pain by administeringnon-opioid compounds which have agonist activity at the μ, δ and κreceptors and which produce less side effects than compounds currentlyavailable.

It is an object of certain embodiments of the present invention toprovide compounds useful as analgesics, anti-inflammatories, diuretics,anesthetics and neuroprotective agents, anti-hypertensives,anti-anxioltics; agents for appetite control; hearing regulators;anti-tussives, anti-asthmatics, modulators of locomotor activity,modulators of learning and memory, regulators of neurotransmitter andhormone release, kidney function modulators, anti-depressants, agents totreat memory loss due to Alzheimer's disease or other dementias,anti-epileptics, anti-convulsants, agents to treat withdrawal fromalcohol and drugs of addiction, agents to control water balance, agentsto control sodium excretion and agents to control arterial bloodpressure disorders and methods for administering said compounds.

The compounds of the present invention are useful for modulating apharmacodynamic response from one or more opioid receptors (ORL-1, μ, δand κ) centrally and/or peripherally. The response can be attributed tothe compound stimulating (agonist) or inhibiting (antagonist) the one ormore receptors. Certain compounds can stimulate one receptor (e.g., a μagonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).

Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. The presentinvention in certain embodiments comprises compounds having the generalformula (I):

wherein W is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkylsubstituted with 1-3 halogen, C₃₋₁₂ cycloalkyl substituted with 1-3halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl- substituted with 1-3 halogen, C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂ cycloalkoxy- substituted with1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-,hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-,—CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-,diaminoalkyl-, -sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a6-membered heteroaromatic ring, a 6-membered heterocyclicC₁₋₄alkyl-, a6-membered heteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a6-membered aromaticC₁₋₄alkyl-, a 5-membered heterocyclic ring optionallysubstituted with an oxo or thio, a 5-membered heteroaromatic ring, a5-membered heterocyclicC₁₋₄alkyl- optionally substituted with an oxo orthio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁, —C₁₋₅(═NH)W₁,—C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, wherein W₁ is hydrogen,C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH,amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a 5-memberedheteroaromatic ring optionally substituted with 1-3 lower alkyl;

wherein each V₁ is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, benzyl and phenyl;

Q is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6membered aromatic or heteroaromatic group;

each n is independently an integer from 0 to 3;

A, B and C are independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,acylamino-, acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or A-B cantogether form a C₂₋₆ bridge, or B-C can together form a C₃₋₇ bridge, orA-C can together form a C₁₋₅ bridge;

Z is selected from the group consisting of a bond, straight or branchedC₁₋₆ alkylene, —NH—, —CH₂O—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—,—NHCH₂CO—, —CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and—HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted orsubstituted with one or more lower alkyl, hydroxy, halo or alkoxy group;

R₁ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino-,C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁, cyano, cyanoC₁₋₁₀alkyl-,cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,benzyl, C₃₋₁₂ cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl orheteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ringsystem, and a Spiro ring system of the formula (III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₀₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀ alkoxy-, and cyano; andwherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, or spiro ring system of the formula (III)is optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substitutedwith an oxo, amino, alkylamino or dialkylamino group;

and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds havingthe formula (IA):

wherein

each n is independently an integer from 0 to 3;

Z is selected from the group consisting of a bond, —CH₂—, —NH—, —CH₂O—,—CH₂CH₂—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH₂CO—,—COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—, wherein the carbonand/or nitrogen atoms are unsubstituted or substituted with a loweralkyl, halogen, hydroxy or alkoxy group;

R₁ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂ cycloalkenyl, a monocyclic, bicyclicor tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, ahetero-bicyclic ring system, and a spiro ring system of the formula(III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, or benzyl is optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy,said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, and cyano;

wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, and spiro ring system of the formula (III)are optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen, said alkyl optionally substituted with an oxogroup;

and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds havingthe general formula (II):

wherein W is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkylsubstituted with 1-3 halogen, C₃₋₁₂ cycloalkyl substituted with 1-3halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl-substituted with 1-3 halogen, C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂ cycloalkoxy-substituted with1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-,hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-,—CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-,diaminoalkyl-, -sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a6-membered heteroaromatic ring, a 6-membered heterocyclicC₁₋₄alkyl-, a6-membered heteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a6-membered aromaticC₁₋₄alkyl-, a 5-membered heterocyclic ring optionallysubstituted with an oxo or thio, a 5-membered heteroaromatic ring, a5-membered heterocyclicC₁₋₄alkyl-optionally substituted with an oxo orthio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁, —C₁₋₅(═NH)W₁,—C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, wherein W₁ is hydrogen,C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH,amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a 5-memberedheteroaromatic ring optionally substituted with 1-3 lower alkyl;

wherein each V, is independently selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, benzyl and phenyl;

Q is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6membered aromatic or heteroaromatic group;

n is an integer from 0 to 3;

A, B and C are independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl,C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,acylamino-, acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or A-B cantogether form a C₂₋₆ bridge, or B-C can together form a C₃₋₇ bridge, orA-C can together form a C₁₋₅ bridge;

Z is selected from the group consisting of a bond, straight or branchedC₁₋₆ alkylene, —NH—, —CH₂O—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—,—NHCH₂CO—, —CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and—HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted orsubstituted with one or more lower alkyl, hydroxy, halo or alkoxy group;

R₁ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino-,C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁, cyano, cyanoC₁₋₁₀alkyl-,cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,benzyl, C₃₋₁₂ cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl orheteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ringsystem, and a spiro ring system of the formula (III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₀₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀ alkoxy-, and cyano; andwherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, or spiro ring system of the formula (III)is optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluorormethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl- and halogen, said alkyl or cycloalkyl optionally substitutedwith an oxo, amino, alkylamino or dialkylamino group;

and pharmaceutically acceptable salts thereof and solvates thereof.

The present invention in certain embodiments comprises compounds havingthe formula (IIA) as follows:

wherein

n is an integer from 0 to 3;

Z is selected from the group consisting of a bond, —CH₂—, —NH—, —CH₂O—,—CH₂CH₂—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH₂CO—,—COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—, wherein the carbonand/or nitrogen atoms are unsubstituted or substituted with a loweralkyl, halogen, hydroxy or alkoxy group;

R, is selected from the group consisting of hydrogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂ cycloalkenyl, a monocyclic, bicyclicor tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, ahetero-bicyclic ring system, and a spiro ring system of the formula(III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂;

wherein said monocyclic aryl is preferably phenyl;

wherein said bicyclic aryl is preferably naphthyl;

wherein said alkyl, cycloalkyl, alkenyl, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, or benzyl is optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy,said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, and cyano;

wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, and spiro ring system of the formula (III)are optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy and benzyloxy are optionally substituted-with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano;

R₂ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen, said alkyl optionally substituted with an oxogroup;

and pharmaceutically acceptable salts thereof and solvates thereof.

In certain preferred embodiments of formula (I) or (II), Q is phenyl ora 6 membered heteroaromatic group containing 1-3 nitrogen atoms.

In certain preferred embodiments of formula (I), (II), (IA) or (IIA),the R₁ alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

In certain preferred embodiments of formula (I), (II), (IA) or (IIA),the R₁ cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, or norbornyl.

In other preferred embodiments of formula (I), (II), (IA) or (IIA), theR₁ bicyclic ring system is naphthyl. In other preferred embodiments offormula (I), (II), (IA) or (IIA), the R₁ bicyclic ring system istetrahydronaphthyl, or decahydronaphthyl and the R₁ tricyclic ringsystem is dibenzocycloheptyl. In other preferred embodiments R₁ isphenyl or benzyl.

In other preferred embodiments of formula (I), (II), (IA) or (IIA), theR₁ bicyclic aromatic ring is a 10-membered ring, preferably quinoline ornaphthyl.

In other preferred embodiments of formula (I), (II), (IA) or (IIA), theR₁ bicyclic aromatic ring is a 9-membered ring, preferably indenyl.

In certain embodiments of formula (I), (II), (IA) or (IIA), Z is a bond,methyl, or ethyl.

In certain embodiments of formula (I), (II), (IA) or (IIA), the Z groupis maximally substituted as not to have any hydrogen substitution on thebase Z group. For example, if the base Z group is —CH₂—, substitutionwith two methyl groups would remove hydrogens from the —CH₂— base Zgroup.

In other preferred embodiments of formula (I), (II), (IA) or (IIA), n is0.

In certain embodiments of formula (I), (II), (IA) or (IIA), X₁ and X₂are both O.

In certain embodiments of formula (I) or (II), W is —CH₂C(═O)NH₂,—C(NH)NH₂, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl,—C(═O)CH₃, —CH₂CH₂NHC(═O)CH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃, furanylcarbonyl-,methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-,trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, ordiazolemethyl-.

In certain embodiments of formula (I) or (II), ZR₁ is cyclohexylethyl-,cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-,phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-,pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-,tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-,thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-,isopropoxybutyl-, hexyl-, or oxocanylpropyl-.

In certain embodiments of formula (I) or (II), at least one of ZR₁ or Wis —CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-,NH₂SOmethyl-, aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, ordiC₁₋₄alkylaminocarbonylmethyl-.

In certain embodiments of formula (I) or (II), ZR₁ is 3,3 diphenylpropyloptionally substituted at the 3 carbon of the propyl with —COOV₁,tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-, C₁₋₄alkylaminocarbonyl-,or diC₁₋₄alkylaminocarbonyl-.

In alternate embodiments ZR₁ in formula (I), (II), (IA) or (IIA) can be

wherein

Y₁ is R₃-(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl, R₆-(C₃-C₁₂)cyclo-alkyl,R₇-(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CN or —C(O)NR₈R₉; Y₂ ishydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; or Y₁, Y₂ and Y₃,together with the carbon to which they are attached, form one of thefollowing structures:

wherein r is 0 to 3; w and u are each 0-3, provided that the sum of wand u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring Eis a fused R₄-phenyl or R₅-heteroaryl ring;

R₁₀ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R and—(C₁-C₆)alkyl-NR₈R₉;

R₁₁ is 1 to 3 substituents independently selected from the groupconsisting of R₁₀, —CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents onadjacent ring carbon atoms may together form a methylenedioxy orethylenedioxy ring;

R₈ and R₉ are independently selected from the group consisting ofhydrogen, (C₁-C₆) alkyl, (C₃-C₁₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl;

R₃ is 1 to 3 substituents independently selected from the groupconsisting of H, R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈ R₉, —OR₁₂ and —S(O)₀₋₂R₁₂;

R₆ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂;

R₄ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁- C₆)alkyl, R₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉,—(C₁- C₆)alkyl-NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —SO₂R₈, —SOR₈, —SR₈, —NO₂,—CONR₈R₉, —NR₉COR₈, —COR₈, —COCF₃, —OCOR₈, —OCO₂R₈, —COOR₈,—(C₁-C₆)alkyl-NHCOOC(CH₃)₃, —(C₁-C₆)alkyl-NHCOCF₃,—(C₁-C₆)alkyl-NHSO₂-(C₁-C₆)alkyl, —(C₁-C₆)alkyl-NHCONH-(C₁-C₆)-alkyl and

wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atomsmay together form a methylenedioxy or ethylenedioxy ring;

R₅ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉,—(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈,—COR₈, —OCOR₈, —OCO₂R₈ and —COOR₈;

R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ or—(C₁-C₆)alkyl-NR₈R₉;

R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈, —(C₁-C₆)alkyl-NR₈R₉,—(C₁-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl;

R₁₃ is 1-3 substituents independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo;

R₁₄ is independently selected from the group consisting of H,(C₁-C₆)alkyl and R₁₃-C₆H₄—CH₂—.

As used herein, the term “alkyl” means a linear or branched saturatedaliphatic hydrocarbon group having a single radical and 1-10 carbonatoms. Examples of alkyl groups include methyl, propyl, isopropyl,butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. A branchedalkyl means that one or more alkyl groups such as methyl, ethyl orpropyl, replace one or both hydrogens in a —CH₂— group of a linear alkylchain. The term “lower alkyl” means an alkyl of 1-3 carbon atoms.

The term “alkoxy” means an “alkyl” as defined above connected to anoxygen radical.

The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbornyl.

The term “alkenyl” means a linear or branched aliphatic hydrocarbongroup containing a carbon-carbon double bond having a single radical and2-10 carbon atoms. A “branched” alkenyl means that one or more alkylgroups such as methyl, ethyl or propyl replace one or both hydrogens ina —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenyl groups includeethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl,2-propenyl, heptenyl, octenyl and decenyl.

The term “cycloalkenyl” means a non-aromatic monocyclic or multicyclichydrocarbon ring system containing a carbon-carbon double bond having asingle radical and 3 to 12 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl. An exemplary multicyclic cycloalkenyl ring isnorbornenyl.

The term “aryl” means a carbocyclic aromatic ring system containing one,two or three rings which may be attached together in a pendent manner orfused, and containing a single radical. Exemplary aryl groups includephenyl, naphthyl and acenaphthyl.

The term “heterocyclic” means cyclic compounds having one or moreheteroatoms (atoms other than carbon) in the ring, and having a singleradical. The ring may be saturated, partially saturated or unsaturated,and the heteroatoms may be selected from the group consisting ofnitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered hetero-monocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asmorpholinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolidinyl. Examples of partially saturated heterocyclic radicalsinclude dihydrothiophene, dihydropyran, and dihydrofuran. Otherheterocyclic groups can be 7 to 10 carbon rings substituted withheteroatoms such as oxocanyl and thiocanyl. When the heteroatom issulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.

The term “heteroaryl” means unsaturated heterocyclic radicals, wherein“heterocyclic” is as previously described. Exemplary heteroaryl groupsinclude unsaturated 3 to 6 membered hetero-monocyclic groups containing1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl, andpyrazinyl; unsaturated condensed heterocyclic groups containing .1 to 5nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated 3to 6-membered hetero-monocyclic groups containing an oxygen atom, suchas furyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining a sulfur atom, such as thienyl; unsaturated 3 to 6 memberedhetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; and unsaturated condensed heterocyclic group containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. Theterm “heteroaryl” also includes unsaturated heterocyclic radicals,wherein “heterocyclic” is as previously described, in which theheterocyclic group is fused with an aryl group, in which aryl is aspreviously described. Exemplary fused radicals include benzofuran,benzdioxole and benzothiophene.

As used herein, the term “heterocyclicC₁₋₄alkyl”,“heteroaromaticC₁₋₄alkyl” and the like refer to the ring structurebonded to a C₁₋₄ alkyl radical.

All of the cyclic ring structures disclosed herein can be attached atany point where such connection is possible, as recognized by oneskilled in the art.

As used herein, the term “patient” includes a human or an animal such asa companion animal or livestock.

As used herein, the term “halogen” includes fluoride, bromide, chloride,iodide or alabamide.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonatessuch as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and thelike.

The invention disclosed herein is also meant to encompass all prodrugsof the disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹p, ³²p, 35S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof: Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well As usedherein, the term “stereoisomers” is a general term for all isomers ofindividual molecules that differ only in the orientation of their atomsin space. It includes enantiomers and isomers of compounds with morethan one chiral center that are not mirror images of one another(diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The term “modulate” as used herein with respect to the ORL-1 receptormeans the mediation of a pharmacodynamic response (e.g., analgesia) in asubject from (i) inhibiting or activating the receptor, or (ii) directlyor indirectly affecting the normal regulation of the receptor activity.Compounds which modulate the receptor activity include agonists,antagonists, mixed agonists/antagonists and compounds which directly orindirectly affect regulation of the receptor activity.

Certain preferred compounds according to the invention of formulae (I)and (IA) include:

-   1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(cyclooctylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;.-   1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(1,3,-dihydroinden-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;-   1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(benzyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(1,2,3,4tetrahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(norbornan-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2, 1    ,3-benzothiadiazin-2,2-dione;-   1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;    and

pharmaceutically acceptable salts thereof and solvates thereof.

Other preferred compounds of formula (I) include:

-   3-butyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-acetamido-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-(2-methanesulfonamido)-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-methoxycarbonylmethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-cyanomethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-(2-hydroxyethyl)-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;-   3-butoxycarbonylmethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;    and

pharmaceutically acceptable salts thereof and solvates thereof.

Certain preferred compounds according to the invention of formula (II)and (IIA) include:

-   1,2,3,4-tetrahydro-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(p-phenylbenzyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(-benzyloxybenzyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one-;-   1,2,3,4-tetrahydro-1-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(norbornan-2-yl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(10,11-dihydro-5H-dibenzo[a.d]-cyclohepten-5-yl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(cyclooctyl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-quinolin-2-one;-   1,2,3,4-tetrahydro-1-[1-(cyclooctylmethyl)-4-piperidinyl]-quinolin-2-one;    and

pharmaceutically acceptable salts thereof and solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention can be administered to anyonerequiring modulation of the opioid and ORL1 receptors. Administrationmay be orally, topically, by suppository, inhalation, or parenterally.

The present invention also encompasses all pharmaceutically acceptablesalts of the foregoing compounds. One skilled in the art will recognizethat acid addition salts of the presently claimed compounds may beprepared by reaction of the compounds with the appropriate acid via avariety of known methods.

Various oral dosage forms can be used, including such solid forms astablets, gelcaps, capsules, caplets, granules, lozenges and bulk powdersand liquid forms such as emulsions, solution and suspensions. Thecompounds of the present invention can be administered alone or can becombined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

When the compounds of the present invention are incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms, are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986). Techniques and compositions for making solid oraldosage forms are described in Pharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz, editors) 2nd edition, published byMarcel Dekker, Inc. Techniques and compositions for making tablets(compressed and molded), capsules (hard and soft gelatin) and pills arealso described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553B1593 (1980). Techniques and composition for making liquidoral dosage forms are described in Pharmaceutical Dosage Forms: DisperseSystems, (Lieberman, Rieger and Banker, editors) published by MarcelDekker, Inc.

When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

In certain embodiments, the compounds of the present invention can beused in combination with at least one other therapeutic agent.Therapeutic agents include, but are not limited to, μ-opioid agonists;non-opioid analgesics; non-steroid antiinflammatory agents; Cox-IIinhibitors; antiemetics; β-adrenergic blockers; anticonvulsants;antidepressants; Ca2+-channel blockers; anticancer agent and mixturesthereof.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination with aμ-opioid agonist. μ-opioid agonists, which may be included in theformulations of the present invention include but are not limited toinclude alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazerie fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

In certain preferred embodiments, the μ-opioid agonist is selected fromcodeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,dihydromorphine, morphine, tramadol, oxymorphone, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

In another embodiment of the invention, the medicament comprises amixture of a Cox-II inhibitor and an inhibitor of 5-lipoxygenase for thetreatment of pain and/or inflammation. Suitable Cox-II inhibitors and5-lipoxygenase inhibitors, as well as combinations thereof are describedin U.S. Pat. No. 6,136,839, which is hereby incorporated by reference inits entirety. Cox-II inhibitors include, but are not limited torofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide, meloxicam,6-MNA, L-745337, nabumetone, nimesulide, NS-398, SC-5766, T-614,L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387,NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxiband parecoxib or pharmaceutically acceptable salts, enantiomers ortautomers thereof.

The compounds of the present invention can also be combined in dosageforms with non-opioid analgesics, e.g., non-steroidal anti-inflammatoryagents, including aspirin, ibuprofen, diclofenac, naproxen,benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam,pharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics which may be included in the dosage formsof the present invention include the following, non-limiting, chemicalclasses of analgesic, antipyretic, nonsteroidal antifinflammatory drugs:salicylic acid derivatives, including aspirin, sodium salicylate,choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylicacid, sulfasalazine, and olsalazin; para-aminophennol derivativesincluding acetaminophen; indole and indene acetic acids, includingindomethacin, sulindac, and etodolac; heteroaryl acetic acids, includingtolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),including mefenamic acid, and meclofenamic acid; enolic acids, includingoxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,oxyphenthartazone); and alkanones, including nabumetone. For a moredetailed description of the NSAIDs that may be included within themedicaments employed in the present invention, see Paul A. InselAnalgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed inthe treatment of Gout in Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon, Eds.,Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic andAnti-Inflammatory Drugs in Remington: The Science and Practice ofPharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th Ed. 1995) which arehereby incorporated by reference in their entireties.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withantimigraine agents. Antimigraine agents include, but are not limitedto, alpiropride, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergot, ergotamine, flumedroxoneacetate,fonazine,lisuride, lomerizine, methysergide oxetorone,pizotyline, and mixtures thereof.

The other therapeutic agent can also be an adjuvant to reduce anypotential side effects such as, for example, an antiemetic agent.Suitable antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzineacethylleucine monoethanolamine, alizapride, azasetron, benzquinamide,bietanautine, bromopride, buclizine, clebopride, cyclizine,dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride,tetrahydrocannabinols, thiethylperazine, thioproperazine, tropisetron,and mixtures thereof.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withP-adrenergic blockers. Suitable p-adrenergic blockers include, but arenot limited to, acebutolol, alprenolol, amosulabol, arotinolol,atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol,bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrinehydrochloride, butofilolol, carazolol, carteolol, carvedilol,celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol,indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol,moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol,oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol,toliprolol, and xibenolol.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withanticonvulsants. Suitable anticonvulsants include, but are not limitedto, acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide,beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withantidepressants. Suitable antidepressants include, but are not limitedto, binedaline, caroxazone, citalopram, dimethazan, fencamine,indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withCa2+-channel blockers. Suitable Ca2+-channel blockers include, but arenot limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil,mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine,aranidipine, barnidipine, benidipine, cilnidipine, efonidipine,elgodipine, felodipine, isradipine, lacidipine, lercanidipine,manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,lormerizine, bencyclane, etafenone, fantofarone, and perhexiline.

In certain embodiments, the compounds of the present invention can beformulated in a pharmaceutical dosage form in combination withanticancer agents. Suitable anticancer agents include, but are notlimited to, acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate;duazornycin; edatrexate; eflornithine hydrochloride; elsamitrucin;enloplatin; enpromate; epipropidine; epirubicin hydrochloride;erbulozole; esorubicin hydrochloride; estramustine; estramustinephosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine;fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;fludarabine phosphate; fluorouracil; flurocitabine; fosquidone;fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea;idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II(including recombinant interleukin II, or rIL2), interferon alfa-2a;interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferonbeta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mrycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene;-sparfosate-sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine.; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; parmidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

The compounds of the present invention and the other therapeutic agentcan act additively or, more preferably, synergistically. In a preferredembodiment, a composition comprising a compounds of the presentinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition orin a different composition from that comprising the compounds of thepresent invention. In another embodiment, a composition comprising thecompounds of the present invention is administered prior to orsubsequent to administration of another therapeutic agent.

The compounds of the present invention when administered, e.g., via theoral, parenteral or topical routes to mammals, can be in a dosage in therange of about 0.01 mg/kg to about 3000 mg/kg body weight of the patientper day, preferably about 0.01 mg/kg to about 1000 mg/kg body weight perday administered singly or as a divided dose. However, variations willnecessarily occur depending upon the weight and physical condition(e.g., hepatic and renal function) of the subject being treated, theaffliction to be treated, the severity of the symptoms, the route ofadministration, the frequency of the dosage interval, the presence ofany deleterious side-effects, and the particular compound utilized,among other things.

The compounds of the present invention preferably have a bindingaffinity K_(i) for the human ORL-1 receptor of about 500 nM or less; 100nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The bindingaffinity K_(i) can be measured by one skilled in the art by an assayutilizing membranes from recombinant HEK-293 cells expressing the humanopioid receptor-like receptor (ORL-1) as described below.

The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1 Synthesis of “5-membered SO₂” Head Groups

Procedure:

1,2-Phenylenediamine 1 (160 g, 1.50 mol) and4-oxo-piperidine-tert-butylester 2 (100 g, 0.50 mol) were dissolved in1,2-dichloroethane (2.0 L) with stirring. Acetic acid (31.6 mL) wasadded, followed by sodium triacetoxyborohydride (148 g, 0.70 mol) andthe resulting mixture stirred at room temperature for 18 hr. The solventwas evaporated and the residue partitioned between ether and 1M aceticacid. The organic layer was separated and washed with 1M acetic acid(3×) followed by sodium bicarbonate solution (1×). The aqueous phaseswere back extracted with ether (1×) and the combined organic extractsdried over MgSO₄, filtered and the solvent evaporated to give an orangegum. Addition of 600 mL of ether/hexane (1:1) followed by seedinginduced crystalization. After 15 min. the mixture was filtered, washedwith 300 mL of ether/hexane (1:1) to give pure 3 as a white solid (79.2g, 53%).

m.p.=107.1-107.6° C. ¹H-NMR (CDCl₃): d 1.30 (bd, 2H), 1.40 (s, 9H), 1.95(bd, 2H), 3.90 (bt, 2H), 3.25 (b, 2H), 3.30 (m, 1H), 3.95 (b, 2H),6.60-6.80 (m, 4H).

The diamine 3 (5.4 g, 18.6 mmol) was dissolved in dry pyridine (30 mL).Sulfamide (3.58 g, 37.2 mmol) was added and the mixture heated to refluxfor 2 h. The mixture was cooled to room temperature and the solventevaporated to dryness. The residue was partitioned betweendichloromethane: methanol (10: 1, 500 mL) and 0.1 M hydrochloric acid(500 mL), the organic phase separated, washed with brine (500 mL), driedovere MgSO₄, filtered and the solvent evaporated. The residue wastriturated with ethyl acetate to give pure 4 as a pale pink solid (5.15g, 79%).

m.p.=204.7°-205.4° C. ¹H-NMR (DMSO): d 1.30 (s, 9H), 1.80-1.95 (m, 4H),2.80 (b, 2H), 3.95 (m, 2H), 4.10 (m, 1H), 6.70-7.00 (m, 4H), 11.25 (bs,1H).

Compound 4(5.15 g, 14.57 mmol) was suspended in 100 mL of ethyl acetate,20 mL of a 1:1 mixture of concentrated hydrochloric acid/ethyl acetatewas added and the suspension stirred at room temperature for 2 h. Themixture was filtered and the filtrate washed with ethyl acetate to givepure 5 (HCl salt) as a pale pink solid (3.82 g, 91%).

¹H-NMR (DMSO) (HCl salt): d 2.10 (m, 2H), 2.50 (m, 2H), 3.12 (m, 2H),3.52 (m, 2H), 4.40 (m, 1H), 5.80 (b, 1H), 6.90-7.20 (m, 3H), 7.35 (m,1H), 9.20 (b, 1H), 9.40 (b, 1H), 11.70 (b, 1H).

Elemental analysis: C₁₁H₁₅N₃O₂S.HCl.0.75H₂O requires: C, 43.56; H, 5.81;N, 13.85. found: C, 43.90; H, 5.78; N, 13.51.

EXAMPLE 2 Synthesis of “6-membered SO₂” Head Groups

Procedure:

Anthranilamide 6 (15.0 g, 110.1 mmol) and N-benzyl-4-piperidone (20.96g, 110.1 mmol) were dissolved in glacial acetic acid (150 mL) withstirring under nitrogen over 15 min. Sodium triacetoxyborohydride (35.14g, 165.8 mmol) was added in portions and the resulting mixture stirredat room temperature for 60 hr. The mixture was poured into water andextracted with ethyl acetate (1×). The ethyl acetate extract was backextracted with water (3×). The combined aqueous extracts were carefullybasified with sodium hydroxide pellets to pH 12 and the mixture filteredto give a white solid that was triturated with acetone to give 7 as awhite crystalline solid (19.8 g, 58%).

mp=249.8-250.7° C. (dec.).

To a suspension of lithium aluminium hydride (3.58 g, 96.7 mmol) in 50mL of dry dioxane was added dropwise a suspension of 7 (10.0 g, 32.3mmol) in 100 mL of dry dioxane. The resulting mixture was stirred for 1hr at room temperature then heated to reflux overnight. The mixture wascooled to room temperature and cautiously quenched with water over 1 hr.Magnesium sulfate (ca 20 g) was added, the mixture filtered throughCelite, and the filter cake washed with dichloromethane. The filtratewas dried over MgSO₄, filtered and evaporated. The residue wastriturated with ether to give pure 8 as a white solid (6.70 g, 71%).

mp=116-118° C. ¹H-NMR (CDCl₃): d 1.60 (m, 2H), 2.10 (m, 2H), 2.25 (bt,2H), 2.85 (b, 2H), 3.40 (m, 1H), 3.60 (s, 2H), 3.91 (s, 2H), 6.63 (m,2H), 7.05 (d, 1H), 7.20 (m, 1H), 7.25-7.4 (m, 5H).

To a solution of 8 (7.00 g, 23.7 mmol) in 50 mL of pyridine was addedsulfamide (4.55 g, 47.4 mmol) and the resulting solution heated toreflux for 18 hr. After cooling to room temperature the mixture wasevaporated to give a brown gum. This was partitioned between chloroformand 1M potassium carbonate solution and the organic phase separated. Theaqueous phase was extracted with chloroform (2×) and the combinedorganic extracts dried over MgSO₄, filtered and evaporated. The residuewas chromatographed to give a pale yellow foam (6.00 g). This wasdissolved in 60 mL of ethyl acetate and 4 mL of a 1:1 mixture ofconcentrated hydrochloric acid: ethyl acetate was added. The mixture wasallowed to stand for 30 min until complete crystallization had occurred.The mixture was filtered and the solid washed with ethyl acetate to givepure 9 as a white crystalline solid (6.28 g, 67%).

mp=248-249.9° C. ¹H-NMR (DMSO) (HCl salt): d 2.05 (m, 2H), 2.32 (m, 2H),3.12 (m, 2H), 3.40 (b, 2H), 4.30 (b, 3H), 4.45 (b, 2H), 7.10-7.30 (m,4H), 7.40-7.60 (m, 5H), 7.85 (m, 1H).

Compound 9 (4.0 g, 11 mmol) was hydrogenated over Pd/C in 100 mL ofmethanol/water (3: 1) for 24 hr. Filtration and evaporation gave aresidue that was triturated with ethyl acetate/methanol (1:1) to givepure 10 as a white crystalline solid (2.72 g, 89%).

MS: m/z 268.1 (M+1) ¹H-NMR (CDCl₃) (HCl salt): d 2.00 (m, 4H), 2.70 (m,2H), 3.2 (m, 2H), 4.15 (m, 1H), 4.52 (s, 2H), 7.15-7.35 (m, 5H).

Elemental analysis: C₁₂H₁₇N₃O₂S.HCl.0.4H₂O requires: C, 46.34; H, 6.09;N, 13.51. found: C, 46.36; H, 5.88; N, 13.37.

EXAMPLE 3 Attachments of Tail Groups to the “5-membered SO₂” and“6-membered SO2” Head Groups.

Tail groups were attached to the head groups according to the followingprocedures:

General Procedure for Alkylation:

To a solution of the amine (1 eq) and triethylamine (1 eq) indimethylformamide, was added 1 eq of alkyl bromide or chloride in oneportion. The mixture was stirred and heated at 80° C. over night. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product. General procedure for reductiveamination:

General Procedure for Reductive Amination:

To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid(1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in oneportion. The mixture was stirred over night at room temperature. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

The following compounds were prepared by attaching the tail groups usingthe general procedures described:

-   1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 93.2% MS: m/z 394.2 (M+1) ¹H-NMR (DMSO): d 1.95 (b, 2H), 2.22 (m,2H), 2.40 (b, 2H), 3.10 (m, 2H), 3.80-4.00 (b, 3H), 6.60-6.80 (m, 4H),7.50 (m, 3H), 7.90 (m, 4H), 10.8 (b, 1H1).

-   1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 96.4% MS: m/z 420.6 (M+1) ¹H-NMR (CDCl₃): d 2.07 (m, 2H), 2.30 (m,2H), 2.48 (m, 2H), 3.15 (m, 2H), 3.65 (s, 2H), 3.90 (m, 1H), 6.78-6.95(m, 4H), 7.30-7.60 (m, 9H).

-   1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 100% MS: nm/z 448.2 (M+1) ¹H-NMR (DMSO): d 2.00 (b, 2H), 2.20-2.40(m, 4H), 2.60-2.85 (m, 4H), 3.20-3.50 (m, 2H), 3.90 (bt, 1H), 4.00 (t,1H), 6.40-6.60 (m, 4H), 7.18 (m, 2H), 7.25-7.40 (m, 8H).

-   1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 98% MS: m/z 450.7 (M+1)

¹H-NMR (CDCl₃): d 2.23 (m, 2H), 2.75 (m, 2H), 2.90 (m, 2H), 3.62 (s,2H), 3.85 (m, 2H), 4.12 (m, 1H), 5.10 (s, 2H), 6.90-7.48 (m, 13H).

-   1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 100% MS: m/z 384.6 (M+1) ¹H-NMR (DMSO-d₆): d 1.20-2.60 (m, 10H),2.75-3.10 (m, 5H), 3.90 (m, 1H), 6.40 (b, 2H), 6.55 (b, 2H), 7.10 (b,4H).

-   1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 92.7% MS: m/z 378.3 (M+1) ¹H-NMR (DMSO-d₆): d 0.85 (t, 3H), 1.15 (m,1H), 1.30 (m, 4H), 1.35-1.55 (m, 2H), 1.55-1.65 (m, 4H), 1.70 (b, 1H),1.85 (b, 1H), 1.90-2.10 (m, 2H), 2.35-2.50 (b, 2H), 3.00 (b, 3H), 3.55(b, 2H), 3.92 (m, 1H), 6.30 (m, 2H), 6.50 (m, 2H), 10.1 (b, 1H).

-   1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 100% MS: m/z 352.3 (M+1) ¹H-NMR (DMSO): d 0.85 (m, 6H), 1.10-1.30(m, 6H), 1.40 (m, 1H), 1.50 (m, 1H), 1.70 (b, 1H), 2.05 (bd, 2H), 2.45(m, 2H), 2.90-3.20 (m, 3H), 3.90-4.10 (m, 2H), 6.30 (m, 2H), 6.50 (m,2H).

-   1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 95% MS: m/z 390.7 (M+1) ¹H-NMR (DMSO-d₆): d 0.8-2.10 (m, 20H),2.90-3.60 (m, 5H), 3.95 (m, 1H), 6.30 (b, 2H), 6.5 0 (b, 2H).

-   1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 100% MS: m/z 364.3 (M+1) ¹H-NMR (DMSO-d₆): d 1.30-2.10 (m, 18H),2.35-2.55 (m, 2H), 2.90-3.40 (m, 3H), 4.00 (m, 1H), 6.30 (m, 2H), 6.50(m, 2H).

-   1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 95.1% MS: m/z 378.3 (M+1) ¹H-NMR (DMSO-d₆): d 0.80-0.95 (m, 6H),1.03 (b, 1H), 1.15 (m, 1H), 1.30-1.50 (m, 2H), 1.55-1.90 (m, 6H), 2.05(b, 2H), 2.30-2.50 (m, 2H), 2.80-3.20 (b, 3H), 3.40-3.60 (b, 2H), 3.95(m, 1H), 6.38 (m, 2H), 6.45 (m, 2H), 7.00 (b, 1H).

-   1-[1-(1,3,-dihydroinden-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 96.5% MS: m/z 370.6 (M+1) ¹H-NMR (DMSO-d₆): d 2.00 (b, 2H), 2.30 (m,2H), 2.70 (m, 2H), 3.10 (m, 2H), 3.20-3.60 (m, 5H), 3.90 (m, 1H),6.40-6.65 (m, 4H), 7.10-7.30 (m, 4H).

-   1-[1-(cyclooctylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione

LC: 100% MS: m/z 392.7 (M+15) ¹H-NMR(MeOH): d 1.30-1.80 (m,14H), 2.05(m, 1H), 2.22 (m, 2H), 2.50 (m, 2H)., 2.85 (m, 2H), 3.00 (m, 2H), 3.60(m, 2H), 4.30 (m, 1H), 4.50 (s, 2H), 7.10-7.40 (m, 4H).

-   1-[1-(benzyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione ¹H-NMR    (DMSO-d₆) of HCl Salt form: d 2.05 (m, 2H), 2.32 (m, 2H), 3.12 (m,    2H), 3.40 (b, 2H), 4.30 (b, 3H), 4.45 (b, 2H), 7.10-7.30 (m, 4H),    7.40-7.60 (m, 5H), 7.85 (m, 1H).-   1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 408.3 (M+1) ¹H-NMR (CDCl₃): d 1.95 (b, 2H), 2.20 (m,4H), 3.05 (m, 2H), 3.70 (s, 2H), 4.10 (m, 1H), 4.50 (s, 2H), 7.10 (m,2H), 7.20 (m, 1H), 7.30 (m, 1H), 7.45 (m, 3H), 7.75 (s, 1H), 7.85 (m,3H).

-   1-[1-p-phenylbenzyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 92.3% MS: m/z 434.1 (M+1) ¹H-NMR (CDCl₃): d 1.95-2.30 (m, 6H), 3.10(b, 2H), 3.65 (s, 2H), 4.10 (M, 1H), 4.50 (s, 2H), 7.10-7.70 (m, 13H).

-   1-[1-(10,11-Dihydro-5H-dibenzo[and]-cyclohepten-5-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 482.2 ¹H-NMR (DMSO): d 1.75 (b, 4H), 1.92 (m, 2H),2.60-2.80 (m, 4H), 3.82 (m, 3H), 4.00 (s, 1H), 4.30 (s, 2H), 7.00-7.40(M, 12H).

-   1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 461.7 ¹H-NMR (DMSO): d 1.75-2.00 (m, 6H), 2.17 (b, 4H),2.82 (m, 2H), 3.85 (m, 1H), 3.95 (m, 1H), 4.35 (s, 2H), 7.05-7.20 (m,5H), 7.22-7.35 (m, 9H).

-   1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1    ,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 464 (M+1) ¹H-NMR (CDCl₃): d 1.90 (m, 2H), 2.10 (m, 4H),2.98 (m, 2H), 3.45 (s, 2H), 4.10 (m, 1H), 4.45 (s, 2H), 5.10 (s, 2H),6.90 (d, 2H), 7.10-7.50 (m, 11H).

-   1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 398.5. (M+1) ¹H-NMR (MeOH-d₄): d 1.75-3.45 (m, 14H),3.60 (m, 1H), 4.30 (m, 1H), 4.50 (s, 2H), 7.10-7.40 (m, 8H).

-   1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 95.1% MS: m/z 391.9 ¹H-NMR (CDCl₃):d 0.90 (m, 4H), 1.20 (m, 1H),1.30 (m, 5H), 1.60-1.95 (m, 6H), 2.00 (m, 2H), 2.17 (m, 2H), 2.30-2.50(m, 3H), 3.20 (m, 2H), 4.10 (m, 1H), 4.50 (s, 2H), 7.15 (m, 2H), 7.23(d, 1H), 7.35 (t, 1H).

-   1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 77.0% MS: m/z 366.2 (M+1) ¹H-NMR (CDCl₃): d 0.85 (d, 6H), 0.95 (d,3H), 1.15-2.15 (m, 9H), 2.22-2.60 (m, 3H), 2.90 (m, 2H), 4.01 (m, 1H),4.50 (s, 2H), 7.08-7.40 (m, 4H).

-   1-[1-(norbornan-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 362.6 (M+1) ¹H-NMR(CDCl₃): d 1.10 (m, 1H), 1.40-1.75(m, 6H), 2.05 (m, 1H), 2.15 (m, 2H), 2.30-2.55 (m, 3H), 2.60 (b, 1H),2.80 (m, 2H), 3.10 (m, 1H), 3.51 (m, 2H), 4.25 (m, 1H), 4.50 (s, 2H),7.20-7.40 (m, 4H).

-   1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 404.2 (M+1) ¹H-NMR (DMSO): d 1.15-1.78 (m, 16H), 1.85(m, 1H), 1.90-2.10 (m, 3H), 2.32 (m, 2H), 2.51 (m, 1H), 2.98 (m, 2H),4.05 (m, 1H), 4.50 (s, 2H), 7.10-7.35 (m, 4H).

-   1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 96.0% MS: m/z 378.5 (M+1) ¹H-NMR (MeOH): d 1.5-2.05 (m, 14H),2.30.(m, 2H), 2.50 (m, 2H), 3.30 (m, 2H), 3.52 (m, 3H), 4.35 (m, 1H),4.50 (s, 2H), 7.10-7.40 (m, 4H).

-   1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 392.2 (M+1) ¹H-NMR (CDCl₃): d 0.90 (m, 5H), 1.12 (m,1H), 1.25 (m, 2H), 1.47 (b, 2H), 1.65 (m, 2H), 1.80-2.00 (m, 3H), 2.18(m, 3H), 2.54 (m, 2H), 3.08 (m, 3H), 3.50 (m, 2H), 4.29 (m, 1H), 4.53(s, 2H), 7.10-7.30 (m, 3H), 7.40 (t, 1H).

-   1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: m/z 384.3 (M+1) ¹H-NMR (DMSO): d 1.78-2.10 (m, 6H), 2.70(m,2H), 2.90-3.10 (m, 5H), 3.89 (m, 1H), 4.35 (s, 2H), 7.00-7.25 (m,8H).

-   3-butyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: 448.4 H-NMR(DMSO): 7.35 t (1H); 7.11-7.23 m (3H); 6.60 s(2H); 4.48 s (2H); 3.88-3.97 m (1H); 3.25 d (2H); 2.95 t (2H); 2.41 bs(1H); 2.25 bs (2H); 1.87 m (4H); 1.65 m (7H); 1.51 m (2H); 1.33 m (4H);0.88 t (3H); 0.81 d (6H)

-   3-acetamido-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-berizothiadiazin-2,2-dione

LC: 100% MS: 449.2 H-NMR(CDCl3): 7.48 s (1H); 7.35 t (1H); 7.25-7.33 m(3H); 6.55 s (2H); 4.51 s (2H); 3.90 m (1H); 3.56 s (2H); 3.18 d (2H);2.45 bs (1H); 2.33 bs (2H); 1.75-1.95 m (4H); 1.50-1.68 m (6H); 1.44 m(1H); 1.33 m (1H); 1.12 m (1H); 0.78 d (6H)

-   3-(2-methanesulfonamido)-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: 513.2 H-NMR(DMSO): 7.09-7.30 m (4H); 6.58 s (2H); 4.54 s(2H); 4.46 d (2H); 3.99 m (4H); 3.12 m (5H); 2.88 s (3H); 2.33 bs (3H);1.98 s (3H); 1.89 m (5H); 1.34 m (6 H); 1.18 m (4H); 1.16 t (2H); 0.82 d(6H)

-   3-methoxycarbonylmethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: 464.2 H-NMR(DMSO): 7.41 m (1H); 7.33 m (3H); 6.67 s (4H);4.65 s (2H); 3.95 s (3H); 3.65 s (3H); 2.49 m (1H); 2.38 m (2H); 2.05 m(2H); 1.77 m (2H); 1.56 m (6H); 1.35 m (2H); 1.25 m (1H); 0.80 d (6H)

-   3-cyanomethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione;.

LC: 100% MS: 431.3 H-NMR(DMSO): 7.10-7.48 m (4H); 4.60 s (2H); 4.45 s(2H); 3.77 m (1H); 2.91 d (2H); 2.25 m (1H); 1.90 t (2H); 1.85 d (2H);1.50-1.66 m (7H); 1.21-1.44 m (5H); 1.07 m (1H); 0.82 d (6H)

-   3-(2-hydroxyethyl)-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: 436.2 H-NMR(CDCl3): 7.38 t (1H); 7.22 m (3H); 6.67 s (2H);4.55 s (2H); 3.95 m (1H); 3.62 m (2H); 3.11 m (4H); 2.44 bs (1H); 2.35bs (2H); 1.85 bs (4H); 1.55-1.65 m (5H); 1.48 m (2H); 1.33 m (2H); 1.12m (1H); 0.82 d (6H)

-   3-butoxycarbonylmethyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione

LC: 100% MS: 506.2 H-NMR(DMSO): 7.31 m (1H); 7.22 m (3H); 4.50 s (2H);3.71 s (3H); 2.90 d (2H); 2.22 m (1H); 1.98 t (2H); 1.80 d (2H);1.50-1.70 m (4H); 1.44-1.58 m (12H); 1.28 m (5H); 1.01 m (1H)0.81 d (6H)

Other compounds within the scope of formula (I) or (IA) of the presentinvention can be synthesized by analogous techniques.

EXAMPLE 4

Nociceptin affinity at the ORL1 receptor for preferred compounds wasobtained using the following assay:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Receptor Biology) were prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000×g for 15 min at 4° C. and pellets resuspended in hypotonic bufferto a final concentration of 1-3 mg/ml. Protein concentrations weredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

Functional SGTPgS binding assays were conducted as follows. ORL-1membrane solution was prepared by sequentially adding finalconcentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin,3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190ml/well) was transferred to 96-shallow well polypropylene platescontaining 10 ml of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at room temperature withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 ml ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty ml/wellscintillation cocktail (BetaScint; Wallac) was added and plates werecounted in a Packard Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISMÔ,V. 3.0 and the results are set forth in table 1 below:

TABLE 1 Nociceptin Affinity Compound calc K_(i) (nM)1-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3- >10,000benzothiadiazin-2,2-dione;1-1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3- >10,000benzothiadiazin-2,2-dione;1-1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3- 4461benzothiadiazin-2,2-dione;1-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3- 7114benzothiadiazin-2,2-dione;1-1-[1-(cyclooctylmethyl)-4-piperidinyl]-2,1,3- 49benzothiadiazin-2,2-dione;1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3- 5102benzothiadiazol-2,2-dione; 1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-3592 benzothiadiazol-2,2-dione;1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3- 357benzothiadiazol-2,2-dione;1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2,1,3- 3454benzothiadiazol-2,2-dione;1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3- 225benzothiadiazol-2,2-dione;1-[1-(1,3,-dihydroinden-2-yl)-4-piperidinyl]-2,1,3- 5670benzothiadiazol-2,2-dione; 1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3- 2297benzothiadiazol-2,2-dione;1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3- 609benzothiadiazin-2,2-dione 1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3-1878 benzothiadiazin-2,2-dione1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3- 9535benzothiadiazin-2,2-dione1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3- 28.7benzothiadiazin-2,2-dione1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3- 35.3benzothiadiazin-2,2-dione1-1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3- 231benzothiadiazin-2,2-dione 1-1-[1-(benzyl)-4-piperidinyl]-2,1,3- 3900benzothiadiazin-2,2-dione; 1-1-[1-(10,11-Dihydro-5H-dibenzo[a,d]- 505cyclohepten-5-yl)-4-piperidinyl]-2,1,3- benzothiadiazin-2,2-dione;1-1-[1-(1,2,3,4-tetrahydronaphthyl)-4-piperidinyl]- 26142,1,3-benzothiadiazin-2,2-dione;1-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3- 40benzothiadiazin-2,2-dione; 1-1-[1-(norbornan-2-yl)-4-piperidinyl]-2,1,3-6329 benzothiadiazin-2,2-dione;1-1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3- 187 benzothiadiazin-2,2-dione;1-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2,1,3- 46benzothiadiazin-2,2-dione.1-[1-(3,3-Bis(phenyl)propyl)-4-piperidinyl]-2,1,3- 83benzothiadiazin-2,2-dione3-butyl-1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3- 18benzothiadiazin-2,2-dione 3-acetamido-1-[1-[4-(2-propyl)-cyclohexyl]-3.9 4-piperidinyl]-2,1,3-benzothiadiazin- 2,2-dione3-(2-methanesulfonamido)-1-[1-[4-(2-propyl)- 5cyclohexyl]-4-piperidinyl]-2,1,3- benzothiadiazin-2,2-dione3-methoxycarbonylmethyl-1-[1-[4-(2-propyl)- 41cyclohexyl]-4-piperidinyl]-2,1,3- benzothiadiazin-2,2-dione3-cyanomethyl-1-[1-[4-(2-propyl)-cyclohexyl]- 334-piperidinyl]-2,1,3-benzothiadiazin-2,2-dione3-(2-hydroxyethyl)-1-[1-[4-(2-propyl)- 7.4cyclohexyl]-4-piperidinyl]-2,1,3- benzothiadiazin-2,2-dione3-butoxycarbonylmethyl-1-[1-[4-(2-propyl)- 63cyclohexyl]-4-piperidinyl]-2,1,3- benzothiadiazin-2,2-dione

EXAMPLE 5 Synthesis of Quinoline Head Groups

Procedure:

To a solution of 1 (5 g, 25.1 mmol) in 125 mL of MeOH at roomtemperature was added NaBH₄ (1.9 g, 50.2 mmol) portionwise and thereaction mixture was stirred for 2 hr. The mixture was evaporated todryness and sat. NH₄Cl solution was added. The mixture was extractedwith EtOAc (5×). The combined organic extracts were dried over K₂CO₃,filtered and evaporated under reduced pressure to give the crude product2 as a white solid. This material was used directly in the next stepwithout further purification.

¹H-NMR (CDCl₃): d 1.40-1.55 (m, 11H), 1.85 (m, 2H), 3.00 (m, 2H), 3.85(m, 3H).

To a solution of 2 (5.05 g, 25.1 mmol) in 50 mL of THF at 0° C. wasadded Et₃N (5.25 mL, 37.6 mmol) and CH₃SO₂Cl (2.14 mL, 27.6 mmol). Thereaction was stirred at room temperature for 2 hr. The resulting mixturewas diluted with ether, washed with sat. NH₄Cl solution (3×), dried overMgSO₄ and evaporated to give the crude product as a solid. Triturationwith hexane gave 3 as an off-white solid (6.30 g, 90% for two steps).

¹H-NMR (CDCl₃): d 1.45 (s, 9H), 1.80 (m, 2H), 1.95 (m, 2H), 3.02 (s,3H), 3.30 (m, 2H), 3.72 (m, 2H), 4.90 (m, 1H).

To a solution of compound 4 (5.00 g, 34.0 mmol) in 500 mL of xylene wasadded NaH (1.63 g, 40.8 mmol) at room temperature. After the addition,the mixture was heated to reflux for 2 hr. After cooling to roomtemperature 3 (11.39 g, 40.8 mmol) was added in one portion. Thereaction mixture was heated to gentle reflux and maintained for 20 hr.The cooled solution was partitioned between brine and EtOAc. The layerswere separated and the aqueous layer extracted with EtOAc (1×). Thecombined organic extracts were dried over MgSO₄, filtered and evaporatedto give the crude 5 as an oil, which was used directly to the next stepwithout purification.

A mixture of concentrated HCl in EtOAc (150 ml, 1:10) was added tocompound 5 (11.2 g, 34.0 mmol) at room temperature. The reaction was,monitored by TLC. When the reaction was complete, water and EtOAc wereadded, the layers separated and the aqueous layer was washed with EtOAc(1×). The organic washings were discarded and the aqueous layer wasbasified with K₂CO₃ and extracted with EtOAc (3×). The organic extractswere dried over MgSO₄, filtered and evaporated to give the crude productthat was purified by column chromatography to give 6 (4.30 g, 55% for 2steps) as a clear glass.

¹H-NMR (CDCl₃): d 1.75 (m, 2H), 2.47-2.88 (m, 8H), 3.20 (m, 2H), 4.35(m, 1H), 7.02 (m, 1H), 7.12-7.25 (m, 3H).

EXAMPLE 6 Attachment of Tail Groups

Tail groups were attached to the quinoline head groups according to thefollowing Procedures:

General Procedure For Alkylation:

To a solution of the amine (1 eq) and triethylamine (1 eq) indimethylformamide, was added 1 eq of alkyl bromide or chloride in oneportion. The mixture was stirred and heated at 80° C. over night. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography-to give the pure product.

General Procedure For Reductive Amination:

To a mixture of ketone or aldehyde (1 eq), amine (1 eq), and acetic acid(1 eq) in methanol, was added sodium cyanoborohydride (1.4 eq) in oneportion. The mixture was stirred over night at room temperature. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

The following compounds were prepared by attaching the tail groups usingthe general procedures described:

-   1,2,3,4-tetrahydro-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-quinolin-2-one

LC: 97.4% MS: m/z 371.2 (M+1) ¹H-NMR (CDCl₃): d 1.70 (m, 2H), 2.20 (m,2H), 2.55 (m, 2H), 2.68 (m, 2H), 2.82 (m, 2H), 3.05 (b, 2H), 3.70 (s,2H), 4.32 (m, 1H), 7.02 (m, 1H), 7.15 (d, 1H), 7.20-7.30 (m, 2H), 7.42(m, 2H), 7.51 (d, 1H), 7.75 (s, 1H), 7.85 (m, 3H).

-   1,2,3,4-tetrahydro-1-[1-(-phenylbenzyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 397.2 (M+1) ¹H-NMR (CDCl₃): d 1.75 (b, 2H), 2.20 (m,2H), 2.60 (m, 2H), 2.72 (m, 2H), 2.85 (m, 2H), 3.08 (b, 2H), 3.62 (s,2H), 4.35 (m, 1H), 7.00-7.70 (m, 13H).

-   1,2,3,4-tetrahydro-1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-quinolin-2-one

LC: 93.6% MS: m/z 475.3 (M+1) ¹H-NMR (CDCl₃): d 1.50 (m, 2H), 1.75 (m,2H), 2.05 (m, 4H), 2.4 (m, 2H), 2.65 (m, 4H), 2.80 (m, 2H), 3.01 (m,2H), 3.90 (t, 1H), 4.35 (m, 1H), 6.90-7.35 (m, 12H).

-   1,2,3,4-tetrahydro-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 427.2 (M+1) ¹H-NMR (CDCl₃): d 1.75 (m, 2H), 2.10 (m,2H), 2.78-2.90 (m, 4H), 2.85 (m, 2H), 3.05 (m, 2H), 3.50 (s, 2H), 4.40(m, 1H), 5.05 (s, 2H), 7.00-7.60 (m, 13H).

-   1,2,3,4-tetrahydro-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one

LC: 98.8% MS: m/z 361.2 (M+1) ¹H-NMR (CDCl₃): d 1.88-2.12 (m, 3H), 2.45(m, 1H), 2.65 (m, 2H), 2.80-2.35 (m, 8H), 3.50-3.75 (m, 3H), 3.90 (m,2H), 4.80 (m, 1H), 7.05-7.55 (m, 8H).

-   1,2,3,4-tetrahydro-1-[1-(4-propyl-cyclohexyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 355.2 (M+1) ¹H-NMR (CDCl₃): d 0.80-2.25 (m, 18H),3.55-3.70 (m, 2H), 2.85-3.30 (m, 6H), 3.45-3.80 (m, 4H), 7.00-7.50 (m,4H).

-   1,2,3,4-tetrahydro-1-[1-(5-methylhex-2-yl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 329.6 (M+1) ¹H-NMR (CDCl₃): d 0.95 (m, 6H), 1.25-1.35(m, 3H), 1.42 (d, 3H), 1.53-1.70 (m, 2H), 2.10 (m, 2H), 3.60 (m, 2H),2.85-3.55 (m, 12H), 7.05-7.40 (m, 4H).

-   1,2,3,4-tetrahydro-1-[1-(norbornan-2-yl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 325.2 (M+1) ¹H-NMR (CDCl₃): d 1.22 (m, 1H), 1.40-1.65(m, 5H), 1.80-2.10 (m, 5H), 2.30 (b, 1H), 2.50 (m, 2H), 2.61 (b, 1H),2.85 (m, 2H), 2.90-3.20 (m, 4H), 3.50 (m, 2H), 4.45 (m, 1H), 7.02 (t,1H), 7.22 (d, 1H), 7.28-7.40 (m, 2H).

-   1,2,3,4-tetrahydro-1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 367.2 (M+1) ¹H-NMR (CDCl₃): d 1.20-2.15 (m, 12H), 3.63(m, 2H), 2.85-3.75 (m, 14H), 4.25-4.45 (m, 2H), 7.05-7.45 (m, 4H).

-   1,2,3,4-tetrahydro-1-[1-(10,11-dihydro-5H-dibenzo[a.d]-cyclohepten-5-yl)-4-piperidinyl]-quinolin-2-one

LC: 100% ¹H-NMR (CDCl₃): d 1.62 (b, 2H), 2.00 (m, 2H), 2.51-2.70 (m,4H), 3.85 (m, 6H), 4.00 (s, 1H), 4.05-4.25 (m, 3H), 7.00-7.30 (m, 12H).

-   1,2,3,4-tetrahydro-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]-quinolin-2-one

LC: 99.3% MS: m/z 425.3 (M+1) ¹H-NMR (CDCl₃): d 1.70 (b, 2H), 2.05 (m,2H), 2.30 (m, 4H), 2.55-2.70 (m, 4H), 2.80 (m, 2H), 3.02 (b, 2H), 4.02(m, 1H), 4.30 (mn, 1H), 7.00 (m, 1H), 7.12-7.35 (m, 13H).

-   1,2,3,4-tetrahydro-1-[1-(cyclooctyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 341.2 (M+1) ¹H-NMR (CDCl₃): d 1.36-1.76 (m, 11H),1.78-1.89 (m, 2H), 1.92-1.95 (m, 2H), 1.98-2.09 (m, 2H), 2.58-2.62 (m,2H), 2.79-2.82 (m, 2H), 3.00-3.08 (m, 3H), 3.28-3.42 (m, 3H), 4.90-4.98(m, 1H), 7.05 (t, 1H), 7.14 (d, 1H), 7.40 (d, 1H), 7.51 (t, 1H).

-   1,2,3,4-tetrahydro-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 355.2 (M+1) ¹H-NMR (CDCl₃): d 0.90-1.05 (m, 6H),1.05-2.30 (m, 13H), 2.60 (m, 2H), 2.80-3.80 (m, 6H), 4.35 (m, 2H), 4.55(m, 1H), 7.05-7.45 (m, 4H).

-   1,2,3,4-tetrahydro-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-quinolin-2-one

LC: 90.4% MS: m/z 347.2 (M+1) ¹H-NMR (CDCl₃): d 1.90 (b, 2H), 2.60 (m,2H), 2.70-3.00 (m, 6H), 3.25 (m, 4H), 3.40 (b, 2H), 3.80 (m, 1H), 4.70(m, 1H), 7.00-7.40 (m, 8H).

-   1,2,3,4-tetrahydro-1-[1-(cyclooctylmethyl)-4-piperidinyl]-quinolin-2-one

LC: 100% MS: m/z 355.3 (M+1) ¹H-NMR (CDCl₃): d 1.15-1.28 (m, 2H),1.39-1.78 (M, 15H), 1.98-2.10 (m, 4H), 2.51-2.68 (m, 4H), 2.79 (t, 2H),2.98 (d, 2H), 4.21-4.31 (m, 1H), 6.95-7.01 (m, 1H), 7.11-7.14 (m, 1H),7.20-7.24 (m, 2H).

Other compounds within the scope of formula (II) or (IIA) of the presentinvention can be synthesized by analogous techniques.

EXAMPLE 7

Nociceptin affinity at the ORL1 receptor for preferred compounds wasobtained using the following assay:

Membranes from recombinant HEK-293 cells expressing the human opioidreceptor-like receptor (ORL-1) (Receptor Biology) were prepared bylysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000×g for 15 min at 4° C. and pellets resuspended in hypotonic bufferto a final concentration of 1-3 mg/ml. Protein concentrations weredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

Functional SGTPgS binding assays were conducted as follows. ORL-1membrane solution was prepared by sequentially adding finalconcentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin,3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 nM HEPES, pH 7.4) on ice. The prepared membrane solution (190ml/well) was transferred to 96-shallow well polypropylene platescontaining 10 ml of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at room temperature withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 ml ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty ml/wellscintillation cocktail (BetaScint; Wallac) was added and plates werecounted in a Packard Top-Count for 1 min/well.

Data was analyzed using the curve fitting functions in GraphPad PRISMÔ,v. 3.0 and the results are set forth in table 2 below:

TABLE 2 Nociceptin Affinity Compound calc K_(i) (nM)1,2,3,4-tetrahydro-1-[1-(naphth-2-yl-methyl)-4-piperidinyl]- 3389quinolin-2-one1,2,3,4-tetrahydro-1-[1-(p-phenylbenzyl)-4-piperidinyl]- >10,000quinolin-2-one 1,2,3,4-tetrahydro-1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-2898 piperidinyl]-quinolin-2-one1,2,3,4-tetrahydro-1-[1-(p-benzyloxybenzyl)-4-piperidinyl]- 3502quinolin-2-one1,2,3,4-tetrahydro-1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4- 176piperidinyl]-quinolin-2-one-1,2,3,4-tetrahydro-1-[1-(4-propyl-cyclohexyl)-4- 1257piperidinyl]-quinolin-2-one1,2,3,4-tetrahydro-1-[1-(5-methylhex-2-yl)-4-piperidinyl]- 505quinolin-2-one 1,2,3,4-tetrahydro-1-[1-(norbornan-2-yl)-4-piperidinyl]-781 quinolin-2-one 1,2,3,4-tetrahydro-1-[1-(decahydro-2-naphthyl)-4- 105piperidinyl]-quinolin-2-one1,2,3,4-tetrahydro-1-[1-(10,11-dihydro-5H-dibenzo[a.d]- 95cyclohepten-5-yl)-4-piperidinyl]-quinolin-2-one;1,2,3,4-tetrahydro-1-[1-(3,3-diphenylpropyl)-4-piperidinyl]- 71quinolin-2-one 1,2,3,4-tetrahydro-1-[1-[4-(1-methylethyl)-cyclohexyl]-4-80 piperidinyl]-quinolin-2-one1,2,3,4-tetrahydro-1-[1-(1,3-dihydroinden-2-yl)-4- 71piperidinyl]-quinolin-2-one1,2,3,4-tetrahydro-1-[1-(cyclooctyl)-4-piperidinyl]- 14 quinolin-2-one

EXAMPLE 8

Affinity at the μ receptor for compounds was obtained according to thefollowing assay:

Mu opioid receptor membrane solution was prepared by sequentially addingfinal concentrations of 0.075 μg/μl of the desired membrane protein, 10μg/ml saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mMNaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membranesolution (190 μl/well) was transferred to 96-shallow well polypropyleneplates containing 10 μl of 20× concentrated stock solutions of agonistprepared in DMSO. Plates were incubated for 30 min at room temperaturewith shaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 μl ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na2HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty μl/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

Data were analyzed using the curve fitting functions in GraphPad PRISM™,v. 3.0 and the results of several compounds are set forth in table 3below:

TABLE 3 Mu Receptor Affinity Compound calc K_(i) (nM)1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3- 91.7benzothiadiazin-2,2-dione1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3- 207benzothiadiazin-2,2-dione1-1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazin- 13762,2-dione; 1-1-[1-(1,3-dihydroinden-2-yl)-4-piperidinyl]-2,1,3- 660benzothiadiazin-2,2-dione.1,2,3,4-tetrahydro-1-[1-(cyclooctyl)-4-piperidinyl]-quinolin- 86 2-one;1,2,3,4-tetrahydro-1-[1-(5-methylhex-2-yl)-4-piperidinyl]- 156quinolin-2-one 1,2,3,4-tetrahydro-1-[1-(norbornan-2-yl)-4-piperidinyl]-957 quinolin-2-one 1,2,3,4-tetrahydro-1-[1-(decahydro-2-naphthyl)-4- 341piperidinyl]-quinolin-2-one

1. A compound of the formula (I):

wherein W is hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy-, C₁₋₁₀alkylsubstituted with 1-3 halogen, C₃₋₁₂cycloalkyl substituted with 1-3halogen, C₃₋₁₂cycloalkylC₁₋₄alkyl- substituted with 1-3 halogen,C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂cycloalkoxy- substitutedwith 1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂,hydroxyC₁₋₁₀alkyl, hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀alkyl-,cyanoC₃₋₁₀cycloalkyl-, —CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-,sulfonylaminoC₁₋₁₀alkyl-, diaminoalkyl-, -sulfonylC₁₋₄alkyl, a6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a6-membered heterocyclicC₁₋₄alkyl-, a 6-memberedheteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a 6-memberedaromaticC₁₋₄alkyl-, a 5-membered heterocyclic ring optionallysubstituted with an oxo or a 5-membered heteroaromatic ring, a5-membered heterocyclicC₁₋₄alkyl- optionally substituted with an oxo, a5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₄(═O)W₁, —C₁₋₅(═NH)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, wherein W₁ is hydrogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, —CH₂OH, amino,C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a 5-membered heteroaromatic ringoptionally substituted with 1-3 lower alkyl; wherein each V₁ isindependently selected from the group consisting of H, C₁₋₆alkyl,C₃₋₆cycloalkyl, benzyl and phenyl; Q is a benzo group; the n of the R₂substituent is an integer from 0 to 3; the n of the sulfone ring is 0;A, B and C are independently hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl,C₁₋₁₀alkoxy, C₃₋₁₂cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,acylamino-, acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or A-B cantogether with the carbon atoms to which they are attached form a C₂₋₆bridge, or B—C can together with the carbon atoms to which they areattached form a C₃₋₇ bridge, or A-C can together with the carbon atomsto which they are attached form a C₁₋₅ bridge; Z is selected from thegroup consisting of a bond, straight or branched C₁₋₆alkylene, —NH—,—CH₂O—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, CH₂CO—,—COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and —HC═CH—, wherein thecarbon and/or nitrogen atoms are unsubstituted or substituted with oneor more lower alkyl, hydroxy, halo or alkoxy group; R₁ is selected fromthe group consisting of C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁, cyano,cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—, —NH₂SO₂C₁₋₄alkyl-,NH₂SOC₁₋₄alkyl-, aminocarbonyl-, C₁₋₄alkylaminocarbonyl-,diC₁₋₄alkylaminocarbonyl-, C₃₋₁₂cycloalkenyl-, a substituted monocyclicaryl, or tricyclic aryl or tricyclic heteroaryl ring, ahetero-monocyclic ring, and a Spiro ring system of the formula (III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, or C₃₋₁₂cycloalkylamino-, of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₀₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀alkyl-, C₁₋₁₀alkoxy-, and cyano; and whereinsaid C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkenyl, monocyclic, or tricyclic aryl,tricyclic heteroaryl ring, hetero-monocyclic ring, or spiro ring systemof the formula (III) is optionally substituted with 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy,wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionallysubstituted with 1-3 substitutents selected from the group consisting ofhalogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, and cyano; R₂ is selected from thegroup consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl and halogen,said alkyl or cycloalkyl optionally substituted with an oxo, amino,alkylamino or dialkylamino group; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein W is —CH₂C(═O)NH₂,—C(NH)NH₂, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl,—C(═O)CH₃, —CH₂CH₂NHC(═O)CH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃, furanylcarbonyl-,methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-,trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, ordiazolemethyl-.
 3. The compound of claim 1, wherein ZR₁ iscyclohexylethyl-, cyclohexylmethyl-, cyclopentylmethyl-,dimethylcyclohexylmethyl-, phenylethyl-, pyrrolyltrifluoroethyl-,thienyltrifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-,methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-,indolylmethyl-, pyrazolpentyl-, thiazolylethyl-, phenyltrifluoroethyl-,or oxocanylpropyl-.
 4. The compound of claim 1, wherein at least one ofZR₁ or W is —CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-,aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, ordiC₁₋₄alkylaminocarbonylmethyl-.
 5. The compound of claim 1, wherein ZR₁is 3,3-diphenylpropyl optionally substituted at the 3 carbon of thepropyl with —COOV₁, tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, or diC₁₋₄alkylaminocarbonyl-.
 6. A compound ofthe formula (IA):

wherein the n of the R₂ substituent is an integer from 0 to 3; the n ofthe sulfone ring is 0; Z is selected from the group consisting of abond, —CH₂—, —NH—, —CH₂O—, —CH₂CH₂—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—,CH₂CONH—, —NHCH₂CO—, CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and—HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted orsubstituted with a lower alkyl, halogen, hydroxyl or alkoxy group; R₁ isselected from the group consisting of C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl,amino, C₁₋₁₀alkylamino, C₃₋₁₂cycloalkylamino, C₃₋₁₂cycloalkenyl, asubstituted monocyclic aryl, or tricyclic aryl or tricyclic heteroarylring, a hetero-monocyclic ring, a tricyclic ring system selected fromdibenzocycloheptyl, and a spiro ring system of the formula (III):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; wherein said cycloalkyl, alkenyl, C₁₋₁₀alkylamino,or C₃₋₁₂cycloalkylamino, is optionally substituted with 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, said phenyl,benzyl, and benzyloxy optionally being substituted with 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,and cyano; wherein said C₃₋₁₂cycloalkyl, C₃₋₁₂cycloalkenyl, or tricyclicaryl, tricyclic heteroaryl ring, hetero-monocyclic ring, and spiro ringsystem of the formula (III) are optionally substituted with, and saidsubstituted monocyclic aryl is substituted with, 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy,nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, whereinsaid phenyl, benzyl, phenyloxy and benzyloxy are optionally substitutedwith 1-3 substituents selected from the group consisting of halogen,C₁₋₁₀alkyl, C₁₋₁₀alkoxy, and cyano; R₂ is selected from the groupconsisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl and halogen, saidalkyl optionally substituted with an oxo group; or a pharmaceuticallyacceptable salt thereof.
 7. A compound of claim 6, wherein R₁ iscycloalkyl selected from the group consisting of cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl.
 8. Acompound of claim 6, wherein R₁ is dibenzocycloheptyl.
 9. A compound ofclaim 6, wherein Z is a bond, methylene, or ethylene.
 10. A compound ofclaim 6, wherein X₁ and X₂ are both O.
 11. A compound selected from thegroup consisting of:1-[1-(naphth-2-yl-methyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(p-phenylbenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(3,3-bis(phenyl)propyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(p-benzyloxybenzyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(4-propylcyclohexyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(5-methylhex-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-[4-(2-propyl)-cyclohexyl]-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(cyclooctylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(1,2,3,4-tetrahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(decahydro-2-naphthyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(1,3,-dihydroinden-2-yl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione;1-[1-(cyclooctyl)-4-piperidinyl]-2,1,3-benzothiadiazol-2,2-dione; andpharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a compound of claim 1 and at least onepharmaceutically acceptable excipient.
 13. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 1. 14. Apharmaceutical composition comprising a compound of claim 6 and at leastone pharmaceutically acceptable excipient.
 15. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 6. 16. A compound ofthe formula (IA):

wherein R₂ is selected from the group consisting of hydrogen,C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl and halogen, said alkyl optionallysubstituted with an oxo group; the n of the R₂ substituent is an integerfrom 0 to 3; the n of the sulfone ring is 0; and ZR₁ is

wherein Y₁ is R₃—(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl,R₆—(C₃-C₁₂)cyclo-alkyl, R₇—(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CNor —C(O)NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; orY₁, Y₂ and Y₃, together with the carbon to which they are attached, formone of the following structures:

wherein r is 0 to 3; c and d are independently 1 or 2; s is 1 to 5; andring E is a fused R₄-phenyl or R₅-heteroaryl ring; R₁₀ is 1 to 3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ and —(C₁-C₆)alkyl-NR₈R₉;R₁₁ is 1 to 3 substituents independently selected from the groupconsisting of R₁₀, —CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents onadjacent ring carbon atoms may together form a methylenedioxy orethylenedioxy ring; R₈ and R₉ are independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈R₉, —OR₁₂ and —S(O)₀₋₂R₁₂; R₃ is 1 to 3substituents independently selected from the group consisting of H,R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈R₉, OR₁₂ and S(O)₀₋₂R₁₂; R₆ is 1 to 3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂; R₄ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —SO₂R₈, —SOR₈, —SR₈, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈,—COCF₃, —OCOR₈, —OCO₂R₈, —COOR₈, —(C₁-C₆)alkyl-HCOOC(CH₃)₃,—(C₁C₆)alkyl-NHCOCF₃, —(C₁C₆)alkyl-NHSO₂—(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NHCONH—(C₁-C₆)alkyl and

wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atomsmay together form a methylenedioxy or ethylenedioxy ring; R₅ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈, —OCOR₈, —OCO₂R₈ and—COOR₈; R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉, or(C₁-C₆)alkyl-NR₈R₉; R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈,—(C₁-C₆)alkyl-NR₈R₉, —C₁-C₆)alkyl-SR₈ or aryl(C₁-C₆)alkyl; R₁₃ is 1-3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo; R₁₄ is independently selected fromthe group consisting of H, (C₁-C₆)alkyl and R₃—C₆H₄—CH₂—; or apharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a compound of claim 16 and at least onepharmaceutically acceptable excipient.
 18. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim 16.